Coxsackievirus A6 Induces Necroptosis for Viral Production

Abstract

Hand, foot, and mouth disease (HFMD) is a febrile exanthematous disease with typical or atypical symptoms. Typical HFMD is usually caused by enterovirus 71 (EV71) or coxsackievirus A16, while atypical HFMD is usually caused by coxsackievirus A6 (CA6). In recent years, worldwide outbreaks of CA6-associated HFMD have dramatically increased, although the pathogenic mechanism of CA6 is still unclear. EV71 has been established to induce caspase-dependent apoptosis, but in this study, we demonstrate that CA6 infection promotes a distinct pathway of cell death that involves loss of cell membrane integrity. Necrostatin-1, an inhibitor of necroptosis, blocks the cell death induced by CA6 infection, but Z-DEVD-FMK, an inhibitor of caspase-3, has no effect on CA6-induced cell death. Furthermore, CA6 infection up-regulates the expression of the necroptosis signaling molecule RIPK3. Importantly, necrostatin-1 inhibits CA6 viral production, as assessed by its ability to inhibit levels of VP1 protein and genomic RNA and infectious particles. CA6-induced necroptosis is not dependent on the generation of reactive oxygen species; however, viral 3D protein can directly bind RIPK3, which is suggestive of a direct mechanism of necroptosis induction. Therefore, these results indicate that CA6 induces a mechanism of RIPK3-dependent necroptosis for viral production that is distinct from the mechanism of apoptosis induced by typical HFMD viruses.

Acyl-Coenzyme A Synthetase Long-Chain Family Member 4 Is Involved in Viral Replication Organelle Formation and Facilitates Virus Replication via Ferroptosis

“…These results are consistent with our previous finding that PARP is cleaved in EV-A71-infected cells; moreover, the viral protein of EV-A71 is not affected by the addition of Q-VD-OPh ( 39 , 40 ). As previously reported ( 41 ), increases in receptor-interacting protein kinase 3 (RIPK3) and phosphorylation of RIPK3 were detected in CV-A6-infected cells, while mixed-lineage kinase domain-like protein (MLKL) was not phosphorylated. These results imply that the induction of necroptosis during CV-A6 infection is independent of MLKL phosphorylation ( Fig.…”

Macrel: antimicrobial peptide screening in genomes and metagenomes

“…Given the dearth of novel antibiotics in recent decades and the rise of antimicrobial resistance, prospecting naturally-occurring AMPs is a potentially valuable source of new antimicrobial molecules ( Theuretzbacher et al, 2019 ). The increasing number of publicly available metagenomes and metatranscriptomes revealed a multitude of microorganisms so far unknown, harboring immense biotechnological potential ( Pascoal, Magalhães & Costa, 2020 ; Bernard et al, 2018 ). This presents an opportunity to use these (meta)genomic data to find novel AMP sequences.…”

Rotavirus activates MLKL‐mediated host cellular necroptosis concomitantly with apoptosis to facilitate dissemination of viral progeny

“…Hepatitis C virus induced hepatocyte death also has been found to occur due to simultaneous activation of apoptosis and necroptosis (Lim et al., 2014). Most recently coxsackievirus B (Zhang, Yu, et al., 2020), Respiratory syncytial virus (RSV) (Santos et al., 2021) and Zika virus (Wen et al., 2021) have also been demonstrated to evoke cell death through activation of necroptosis machinery. Interestingly, for almost all the viruses that induce necroptosis, necroptotic cell death was found to be involved in aggravation of disease pathogenesis.…”